Tertiary 2-phenoxy-2-phenylethylamines constitute the subject matter of U.S. Pat. No. 3,106,564. The compounds are said to be useful pharmacological agents exhibiting activity on the central nervous system including useful application as analeptic agents without significant effect on respiration. The compounds are also said to have a high order of activity as antihistaminic and anticholinergic agents. Several tertiary 3-phenoxy-3-phenylpropylamines and quaternary ammonium compounds useful as mydriatic agents are disclosed in J. Pharmaceutical Society, Japan, 93, 508-519, 1144-53, 1154-61 (1973).
The use of 3-substituted phenoxy-3-phenyl dimethylamines in treating depression is claimed in applicants' U.S. Pat. No. 4,018,895 issued Apr. 19, 1977 and pharmaceutical formulations containing 3-substituted phenoxy-3-phenyl dimethylamines as the active ingredient are claimed in applicants' U.S. Pat. No. 4,194,009 issued Mar. 18, 1980. Both of these applications were divisions of Ser. No. 432,379, the grandparent of this application, now U.S. Pat. No. 4,314,081.
Ser. No. 432,379 disclosed compounds of the following structure ##STR1## wherein each R.sup.1 is independently H or methyl and R is naphthyl or ##STR2## wherein R" and R'" are halo, CF.sub.3, C.sub.1-4 alkyl, C.sub.1-3 alkoxy or C.sub.3-4 alkenyl and n and m or 0, 1 or 2. The use and formulation claims of U.S. Pat. Nos. 4,018,895 and 4,194,009 specify an active drug of the identical structure, but the claims of U.S. Pat. No. 4,314,081 cover secondary amines of the formula ##STR3## wherein R.sup.1 has its previous scope but R is m or p-chlorophenyl, O, m or p-anisyl, phenyl, o or m-fluorophenyl, o or p-tolyl, 2,4-difluorophenyl or p-trifluoromethylphenyl. These claimed secondary amines each had unusually high activity in inhibiting uptake of serotonin (5HT) and norephinephine (NE) with less effect on dopamine uptake. Three compounds coming within the scope of claim 1 of the patent have been placed on clinical trial in humans as antidepressants. Two of these have been primarily NE uptake inhibitors, (a majority of the marketed antidepressant drugs increase NE concentrations in brain tissue by uptake inhibition or other mechanisms). The third drug, fluoxetine, --3-phenyl-3-(p-trifluoromethyl)phenoxypropyl methylamine--is a selective 5HT uptake inhibitor; ie., the ratio of the 50% inhibitory concentrations for 5HT uptake vs NE uptake was 0.06 to 20 or about 333 to 1. (See the top compound in Table 2 in any of the above referenced patents). No drug had previously been found with such selectivity for blocking 5HT uptake. Fluoxetine has proved to be a highly potent antidepressant in humans.
Among the dimethylamines covered by formula I above are several with a similar very high 5HT/NE uptake inhibition ratio or with a very low ratio. It is the purpose of this application to specify and claim these drugs.